What are the benign causes of elevated immunoglobulin (Ig) A, G, and M levels?

Benign Causes of Elevated Immunoglobulins

Chronic infections, autoimmune diseases, and chronic inflammatory states are the primary benign causes of elevated IgA, IgG, and IgM levels, with chronic pulmonary infections like bronchiectasis being among the most common culprits. 1

Chronic Infections and Inflammatory States

Chronic pulmonary infections, particularly bronchiectasis, commonly produce polyclonal rises in serum IgG and IgA as a response to ongoing infection and inflammation. 1 This represents persistent antigenic stimulation driving continuous plasma cell production of multiple immunoglobulin types. 1

• Chronic inflammatory states trigger sustained B-cell activation leading to broad-based immunoglobulin elevation across multiple classes. 1
• The polyclonal nature distinguishes these benign elevations from monoclonal gammopathies associated with malignancy. 1

Autoimmune Diseases

Autoimmune Hepatitis

• Autoimmune hepatitis characteristically shows polyclonal hypergammaglobulinemia with elevated IgG (>1.5 times upper limit of normal in 85% of cases), which serves as a major diagnostic criterion. 1, 2
• Liver function tests including transaminases, bilirubin, and anti-nuclear antibodies should be ordered when this is suspected. 1

Autoimmune Thyroiditis

• Autoimmune thyroiditis can present with elevated immunoglobulin levels and should be evaluated with anti-TPO antibodies. 1, 2

Primary Sclerosing Cholangitis

• Elevated IgG levels have been noted in 61% of PSC patients, most often to a level up to 1.5 times upper limit of normal. 3
• Increased IgM levels have been reported in up to 45% of PSC cases. 3

IgG4-Related Disease

• Some patients with IgG4-related disease (10.1%) have elevated serum IgA levels despite the typical expectation of normal or low IgA. 4
• These patients show good response to glucocorticoids, less frequent relapse, and mildly elevated C-reactive protein levels. 4

Isolated IgM Elevation

Isolated elevated IgM with normal IgG and IgA can occur in several benign conditions beyond the primary hyper-IgM syndromes. 5

• Autoimmune hemolytic anemia characteristically shows IgM abnormalities. 5
• Cryoglobulinemia presents with elevated IgM levels. 5
• Primary biliary cirrhosis demonstrates IgM elevation as a characteristic feature. 5

Diagnostic Approach to Distinguish Benign from Pathologic Causes

Initial Laboratory Assessment

• Measure inflammatory markers including C-reactive protein and ESR to assess underlying inflammation. 1
• Perform serum protein electrophoresis (SPEP) to distinguish polyclonal from monoclonal patterns. 1
• Order immunofixation electrophoresis if monoclonal protein is suspected to confirm whether the increase is truly polyclonal. 1

Targeted Testing Based on Clinical Suspicion

• Liver function tests (transaminases, bilirubin, anti-nuclear antibodies) for suspected autoimmune hepatitis. 1
• Anti-TPO antibodies for autoimmune thyroiditis evaluation. 1, 2
• Lymphocyte subset analysis and functional antibody testing if immunodeficiency is suspected. 1

Critical Distinction

• Check serum total protein and albumin levels—concurrent low total protein and albumin strongly suggest secondary hypogammaglobulinemia from protein loss, whereas primary immunodeficiencies typically have normal albumin and total protein. 6

Important Clinical Caveats

A common pitfall is assuming all elevated immunoglobulins indicate malignancy or serious pathology. The polyclonal pattern on SPEP is key to identifying benign causes. 1

• Normal or near-normal levels of one immunoglobulin class do not exclude significant pathology in another class. 3
• Autoantibodies (pANCA, ANA, SMA) may be present in PSC but have low specificity and should not be used as primary diagnostic tools. 3
• Very high IgG levels (>1.5 times upper limit) may predict more severe disease course in certain conditions like atopic dermatitis. 2

Polyclonal hypergammaglobulinemia, even when benign in origin, increases risk of infections, thrombosis, and bone disorders including osteoporosis and fractures. 1, 2 This means that even "benign" elevations require clinical monitoring and may have prognostic implications. 7